Testosterone Enanthate Mental Health and Mood Impact

Does testosterone enanthate improve mood?

In randomized trials, testosterone's effect on mood and depressive symptoms is small and inconsistent, and it is not an established treatment for depression. A 2008 review of the testosterone and depression literature concluded that studies do not support a consistent relationship between testosterone level and mood, that randomized trial results conflict, and that most trials do not support testosterone as a broadly effective antidepressant, though it may help selected groups such as hypogonadal men and men whose depression has not responded to antidepressants [6].

Two regulatory points frame the question. Intramuscular testosterone enanthate is approved for replacement in men with hypogonadism from testicular failure or from pituitary or hypothalamic causes, not for mood [1]. And FDA states that none of the approved testosterone products are approved for men with low testosterone who lack an associated medical condition [7].

What the label lists for mood and mental health

The testosterone enanthate label lists anxiety and depression under Nervous System adverse reactions, alongside increased or decreased libido, headache and generalized paresthesia [1]. Its Drug Abuse and Dependence section goes further. Serious psychiatric manifestations reported in people who abuse anabolic androgenic steroids include major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression, and hypomania and irritability have also been reported in men [1]. The same section says men taking supratherapeutic doses may have withdrawal symptoms lasting weeks to months after abrupt discontinuation, including depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia and decreased libido, and that drug dependence at approved doses has not been documented [1].

The severe psychiatric picture in the label is tied to abuse and to supratherapeutic doses. Anxiety and depression sit in the general adverse-reaction list.

The meta-analysis: 27 trials, 1,890 men

Walther and colleagues pooled 27 randomized placebo-controlled trials in 1,890 men, hypogonadal or eugonadal, who reported depressive symptoms on validated scales [2]. Testosterone treatment reduced depressive symptoms compared with placebo, with a Hedges g of 0.21 (95% CI 0.10 to 0.32). Men on testosterone were more likely to have a 50% or greater reduction in symptom scores (odds ratio 2.30, 95% CI 1.30 to 4.06), and dropout for any reason did not differ significantly from placebo (odds ratio 0.79, 95% CI 0.61 to 1.01) [2]. The authors also tested whether testosterone status, depression status, age, treatment duration and dose changed the size of the effect [2].

An effect of 0.21 on a standardized scale is small.

The largest trial used a gel, not an injection

Seven hundred ninety men aged 65 or older with a serum testosterone below 275 ng/dL were assigned to testosterone gel or placebo gel for one year, with each man enrolled in one or more of a sexual function, physical function or vitality trial [4]. Sexual activity, sexual desire and erectile function all improved significantly with testosterone [4]. Vitality did not: testosterone gave no significant benefit on the Functional Assessment of Chronic Illness Therapy-Fatigue scale, and the share of men who improved walking distance by at least 50 meters differed only when all three trials were pooled (20.5% vs 12.6%, P=0.003) [4].

The investigators reported that men who received testosterone had slightly better mood and lower severity of depressive symptoms than men who received placebo, and concluded that one year of treatment had a moderate benefit for sexual function, some benefit for mood and depressive symptoms, and no benefit for vitality [4].

An enanthate trial in depressed men

Seidman and colleagues ran a 6-week double-blind trial in men with major depressive disorder and a total testosterone of 350 ng/dL or less. Thirty men were randomized, 13 to testosterone enanthate 200 mg intramuscularly each week and 17 to a sesame oil placebo; mean baseline HAM-D was 21 [3]. Both groups improved by about the same amount, a 10.1-point fall on testosterone and 10.5 points on placebo, with no significant difference between groups. Response rates were 38.5% (5 of 13) and 41.2% (7 of 17) [3]. Sexual function improved marginally on testosterone (p=.02) [3].

That is a small, short trial in a narrow group, and its result differs from the meta-analysis average.

Irritability, aggression and high doses

Pope and Katz compared 88 athletes using anabolic steroids with 68 nonusers. Twenty-three percent of users reported a major mood syndrome, meaning mania, hypomania or major depression, in association with steroid use. Users reported mood disorders during steroid exposure significantly more often than in its absence (P<.001) and more often than nonusers (P<.01) [8].

Those participants were athletes using anabolic steroids, so the findings do not establish the effect of prescribed testosterone-enanthate replacement [8]. A controlled study in 28 eugonadal men given a single 1000 mg intramuscular injection of testosterone undecanoate found minor mood changes: anger-hostility rose from a baseline mean of 7.48 to 10.71 at week 2, fatigue-inertia was lower with testosterone than placebo (6.21 vs 7.84), and the authors found no increase in aggressive behavior [9]. Testosterone undecanoate is a different ester from enanthate, and these men did not have hypogonadism.

Memory and dementia risk

Observational data link low testosterone to later dementia. In the French Three-City cohort, 3,650 men aged 65 and older were followed and 105 incident dementia cases were compared with a random sample of 413 men. Each standard-deviation decrease in bioavailable testosterone was associated with a hazard ratio for dementia of 1.29 (95% CI 1.03 to 1.62), and the relationship with total testosterone was reverse J-shaped, with a hazard ratio of 2.33 (P=.026) in the lowest tertile compared with the middle tertile [10]. These are associations in a cohort study, not evidence that treatment prevents dementia [10].

What gets checked

The Endocrine Society's 2018 guideline recommends monitoring symptoms, serum testosterone, hematocrit and prostate cancer risk during the first year of testosterone therapy [5]. It also recommends against starting therapy in men with untreated severe sleep apnea, uncontrolled heart failure, or a heart attack or stroke within the previous 6 months, among other conditions [5].